Peptides and proteins play critical roles in the regulation of biological processes. Peptides, for example, play a regulatory role as hormones and inhibitors, and are also involved in immunological recognition. The significant biological role of peptides makes it important to understand their interactions with the receptors to which they bind.
The determination of the receptor-bound conformation of a peptide is invaluable for the rational design of peptide analogs. Marshall et al, Ann. Rep. Med. Chem., 13:227-238 (1978) disclose that peptides are characteristically highly flexible molecules, the structures of which are strongly influenced by the environment in which they reside. Thus, peptides are not generally useful for determining their receptor-bound conformation.
As no approach is available to predict which new ligand-receptor interactions will lead to antagonists and which will lead to agonists of greater or less potency, it is necessary to perform classical structure-function studies in a systematic way to provide information about the specific amino acid residues and functional groups in a peptide that are important to biological activity. Studies of this nature can utilize conformationally constrained peptide mimetics. For example, Hruby, Trends Pharmacol. Sci., 8:336-339 (1987) suggests that conformational constraints can provide information about the different requirements that a receptor has for a ligand to be an agonist or antagonist.
Generally, peptide mimetics can be defined as structures which serve as appropriate substitutes for peptides in interactions with receptors and enzymes. The development of rational approaches for discovering peptide mimetics is a major goal of medicinal chemistry. Such development has been attempted both by empirical screening approaches and by specific synthetic design. Specific design of peptide mimetics has utilized both peptide backbone modifications and chemical mimics of peptide secondary structures. The beta-turn has been implicated as an important site for molecular recognition in many biologically active peptides. Consequently, peptides containing conformationally constrained mimetics of beta-turns are particularly desirable.
There is a need in the art for new GLP-1 receptor agonist compounds that have good stability, resistance to degradation, and good glucagon-like peptide-1 (GLP-1) receptor binding activity and in vivo glucose lowering activity. To solve these needs, the disclosure herein provides, among other things, novel N-terminus conformationally constrained compounds, novel N-terminus conformationally constrained GLP-1 receptor agonist compounds containing modifications, such as peptide mimetics and/or amino acid substitutions, that provide a conformationally constrained N-terminus that results in improved GLP-1 receptor binding and in vivo blood glucose lowering activity.